Introduction

Legionella is a common cause of atypical community-acquired pneumonia in both immunosuppresed and immunocompetent patients, requiring intensive care unit admission in many cases. Legionella pneumophila causes approximately 90% of all legionellosis and between 70% - 90% of Legionnaires ’ disease is caused by Legionella pneumophila serogroup 1 ⁽¹⁾. Legionnaires’ disease can develop into life-threatening pneumonia that might cause significant morbidity and mortality if not diagnosed and treated correctly. Clinical features do not differentiate Legionella infection from other types of pneumonia, although several clinical and nonspecific laboratory findings may suggest the diagnosis ⁽²⁾.

Case Report

An 85-year-old man was admitted to the hospital for generalized weakness, fever and confusion for 2 days. His past medical history was remarkable for hypertension, chronic obstructive pulmonary disease, atrial fibrillation, benign prostatic hypertrophy, degenerative joint disease and gastroesophageal reflux disease. His family denied any recent travel, exposure to bodies of water or contact with ill people.

Vital signs on admission were: blood pressure of 195/93 mmHg, heart rate of 109 beats/minute, respiratory rate of 34 breaths/minute and temperature of 103.8ºF. Oxygen saturation was 84% breathing room air that improved to 94% while receiving oxygen at 3 liters/minute by nasal canula. Physical examination showed a well-nourished white male, confused and tachypneic. Auscultation of the heart and lungs showed irregularly irregular rhythm and bilateral rales, respectively. Neurological examination showed no focal deficits. There was no cyanosis or clubbing.

Initial complete blood cell count results showed a white blood cell count of 24,600/mm³ [4,000 – 11, 000], a hemoglobin level of 14.8 g/dl [11 – 16] and a platelet count of 215,000/mm³ [160 – 400]. Relevant serum chemistry results included a sodium level of 143 mEq/L [135 – 145], a bicarbonate level of 19 mEq/L [24 – 30] and a creatinine level of 1.1 mg/dl [0.6 – 1.3]. Aspartate aminotransferase level was 303 units/L [10 – 37], an alanine aminotransferase level was 165 units/L [5 – 37], an alkaline phosphatase level was 426 units/L [56 - 155], a total bilirrubin level was 1.5 mg/dl [0.2 – 1.1] and a lactate dehydrogenase level was 581 units/L [60 – 200]. Phosphate level was decreased to 1.9 mg/dl [2.5 – 4.2] and a creatine kinase level was 601 units/L [38 – 174]. Arterial blood gas result showed a pH of 7.49 [7.35 – 7.45], a pCO₂ of 26 mmHg [35 – 45] and a pO₂ of 120 mmHg [85 – 100], with the patient breathing oxygen at 3 liters/minute by nasal canula. Chest radiography demonstrated a right middle lung density (Figure 1), and intravenous ceftriaxone (1 g Q24h) was initiated for possible pneumonia.

Figure 1

Figure 1: Chest radiography showing right middle lung density.

Computed tomography (CT) of the head did not show any abnormalities. Lumbar puncture was performed and cerebrospinal fluid analysis was within normal limits. Blood, urine and cerebrospinal fluid cultures were negative. His medical condition deteriorated with the development of severe hypoxemic respiratory failure and persistent fevers, for which the patient was placed on mechanical ventilation and transferred to the medical intensive care unit. Intravenous ceftriaxone was substituted for vancomycin (1 g Q24h) and piperacillin/tazobactam (2.25 g Q8h) due to worsening infiltrates on the chest radiographies. CT of the chest showed a dense consolidation with air bronchograms in the right upper lobe, lateral segment of the right middle lobe and right lower lobe (Figure 2).

Figure 2

Figure 2: Chest CT demonstrating dense consolidations with air bronchograms in the right upper lobe, lateral segment of right middle lobe and right lower lobe.

On hospital day 3, intravenous azithromycin (500 mg Q24h) was added to the antimicrobial regimen because of a positive urine antigen and respiratory culture results for Legionella pneumophila serogroup 1. Due to persistent fevers, azithromycin was substituted for intravenous moxifloxacin (400 mg Q24h), that was later changed to oral doxycycline (100 mg Q12h) because of a non-sustained ventricular tachycardia and QTc interval abnormalities. Catheter-related bloodstream infection (vancomycin-resistant Enterococcus faecium) and ventilator-associated pneumonia (Acinetobacter baumannii) developed. Vancomycin and piperacillin/tazobactam were discontinued, and intravenous linezolid (600 mg Q12h) and ampicillin/sulbactam (3 g Q8h) were initiated, based on blood and respiratory cultures sensitivity results. His medical condition improved after several days of therapy. However, the patient failed multiple spontaneous breathing trials and a tracheostomy procedure was performed on hospital day 14. He was subsequently transferred to a chronic care facility for rehabilitation purposes.

Discussion

Legionella spp. are gram-negative, intracellular bacteria found in freshwater environments. The genus of Legionella was established in 1979, after a large outbreak of pneumonia ^{(3, 4)}. About 48 species comprising 70 distinct serogroups in the genus Legionella have been identified, with more than half of then been associated with human disease, especially Legionella pneumophila serogroup 1. Legionellosis classically presents as two different clinical entities: Legionnaires’ disease, a severe multisystemic illness causing pneumonia, and Pontiac fever, a self-limited flu-like illness ^{(3, 5, 6, 7)}.

Legionnaires’ disease is transmitted from the environment to humans by inhalation of an infectious aerosol and, in few cases, by microaspiration of contaminated water into the lungs ^{(8, 9)}. Cooling towers, air conditioning units, ventilators, nebulizers and whirlpool baths have been described as sources of water contaminated with Legionella spp. ⁽¹⁰⁾. ^{The primary feature of the pathogenesis of Legionella spp. is their ability to multiply intracellularly. Most cases occur sporadically, but outbreaks of legionellosis are not infrequent (3).}

Legionella-associated pneumonia is commonly seen in patients with some degree of immunosupression. Identified risk factors for Legionnaires’ disease include increased age (>50), smoking, male sex, chronic lung and heart diseases, hematological malignancies, end-stage renal disease, organ transplantation, use of immunosuppressive drugs (steroids, cytotoxic agents), lung cancer, diabetes mellitus and HIV infection ^{(7, 11, 12)}.

The clinical diagnosis of Legionnaires’ disease is difficult. Among hospitalized patients with community-acquired pneumonia, Legionella has been found to be the etiologic agent in about 2% - 14% of cases ⁽¹³⁾. Clinical features in patients with Legionnaires’ disease include fever, non-productive cough, dyspnea, myalgias, arthralgias, abdominal pain with loose stools and diarrhea, central nervous system (CNS) abnormalities (headache, confusion, encephalopathy) and relative bradycardia ^{(14, 15, 16, 17)}. About 50% of patients with Legionella-associated pneumonia develop respiratory failure, the most common complication of Legionnaires’ disease ⁽¹⁸⁾. Although there are a wide variety of non-specific laboratory tests associated with legionellosis, it is difficult to differentiate Legionnaires’ disease from other causes of community-acquired pneumonia using a single nonspecific laboratory test individually. However, when combined, nonspecific laboratory tests increase diagnostic specificity ⁽¹⁹⁾.The most common laboratory abnormalities are hypophosphatemia, hyponatremia, transient elevation of liver enzymes, elevated serum ferritin, increase creatine kinase, elevated C-reactive protein, elevated serum procalcitonin and microscopic hematuria ^{(14, 17, 20, 21)}.

The chest radiography pattern in Legionnaires’ disease is nonspecific. Legionella pneumonia is typically associated with rapidly progressive asymmetrical infiltrates, which may get worse while on appropriate antimicrobial therapy. Pleural effusions and pneumothoraces have also been reported ^{(17, 22)}. Chest CT findings in patients with legionellosis include bilateral and/or unilateral multilobar or multisegmental consolidations, mixed lesions with peribronchovascular foci of consolidation and ground-glass appearance and, occasionally, cavitary lesions in patients receiving high-dose steroids ^{(23, 24)}.

No currently available test is able to diagnose all Legionella spp. in a timely fashion with a high degree of sensitivity and specificity ⁽²⁵⁾. Culture remains the gold standard for diagnosis of legionellosis and is the most specific diagnostic procedure, with a sensitivity of about 60% and specificity of 100%. Legionella spp. can be isolated from a number of specimens, including blood, lung tissue, respiratory secretions and stool. Respiratory secretions are considered the specimen of choice ^{(3, 26, 27)}. Microscopic examination of specimens using direct fluorescent antibody (DFA) staining is helpful in detecting Legionella infections, but cross-reactions with non-Legionella bacteria have been reported ^{(28, 29)}. The most commonly used diagnostic test is the detection of Legionella using urinary antigen testing, which permits early diagnosis and initiation of appropriate antimicrobial therapy. It is considered to be specific for Legionella pneumophila serogroup 1. Therefore, total dependence on this diagnostic assay may miss many cases of legionellosis. An evaluation of the urinary antigen testing by radioimmunoassay (RIA) for the diagnosis of Legionella pneumophila serogroup 1 infection has a sensitivity of about 80% - 90% and specificity of 100%, although the sensitivity of urinary antigen detection appears to be associated with the clinical severity of the disease ^{(3, 30, 31, 32)}. ^{The addition of Legionella pneumophila-specific PCR to a urinary antigen test is useful for diagnosis in patients with suspected Legionnaires’ disease. PCR and the urinary antigen test are able to provide a diagnosis in a time frame that is helpful in the acute stage of the disease, since early recognition of patients with Legionnaires’ disease is essential (33). Occasionally, cytological examination of bronchoalveolar fluid can be helpful for the diagnosis of legionellosis. The presence of lymphoblasts associated with marked neutrophilia is the cytological hallmark finding in the bronchoalveolar lavage (BAL) analysis in patients with suspected Legionnaires’ disease (34).}

Empiric initial therapy for hospitalized patients with community-acquired pneumonia should always include coverage for Legionella spp., because delays in starting appropriate treatment has been associated with increased mortality ⁽³⁵⁾. Antimicrobial agents that achieve high intracellular concentrations are more effective in treating legionellosis. Macrolides, quinolones and tetracyclines are used to treat infections caused by Legionella spp. ⁽³⁶⁾. ^{Cardiac safety of antimicrobial agents is of particular concern in the elderly population, since increased risk of QTc interval prolongation and ventricular arrhythmias has been associated with the use of macrolides and fluoroquinolones (37). Nevertheless, there are some advantages when a quinolone is choose over a macrolide to treat Legionnaires’ disease, such as shorter time to defervescence, more rapid achievement of clinical stability, decreased rate of complications and a shorter hospital stay. Some authors recommend the use of rifampin for combination therapy with macrolides or quinolones in cases of severe disease, but there is no convincing evidence of its effectiveness (38, 39). The duration of therapy has to be decided on an individualized basis. Clinical judgment must be used to establish the optimal length of treatment, but usually a 7 – 14 day course of therapy is sufficient to cure most patients. However, duration of treatment may need to be longer for patients with lung abscesses, empyema, endocarditis or extrathoracic infection (25, 40). Unfortunately, our patient did not received an appropriate initial empiric antimicrobial therapy that should include coverage for atypical organisms, with either macrolide or a quinolone agent. Therapy to target Legionella spp. was initiated on day 3 of admission, when clinical deterioration was evident and after Legionella pneumophila was recovered from urine and respiratory secretions.}

In conclusion, rapid clinical diagnosis of Legionnaires’ disease is important in selecting effective antimicrobial therapy in patients with pneumonia, since an unrecognized Legionella-associated pneumonia carries a high morbidity and mortality. An appropriate initial antimicrobial treatment in patients with community-acquired pneumonia should include a quinolone or a macrolide agent, in order to empirically cover atypical organisms such as Legionella.